Application of cellulose derivatives



vat

wholly composed of Patented Apr. 1, 1941 APPLICATION OF CELLULOSEDERlVATiVES Vincent Jerome Flynn, Brooklyn. N. Y., assignor to WardlynCorporation, Union City, NHL, a

corporation of New Jersey 'No Drawing. Application-September 29, 1938,

Serial N0. 232,407

8 Claims.

This invention relates to compositions of tubes of varying size, shapeand length partially or organic derivatives, either solider hollow, orcirculanoval, elliptical, square, rectangular or of othercross-sectional shape, and in general, to surgical devices comprehendedunder the terms exploratory and evacuative, as catheters, sounds orcannulae, being when solid, intended for distending a passage, and whenhollow for insertion into a normal opening of the body for injection orwithdrawal of fluids therein or therefrom and for medicamentation, or.for insertion into an incision as in post-operative work, for drainageand other purposes.

By the term catheter as herein applied, is to be understood ascomprehending the various sizes, shapes and lengths of (usually) hollowconstruction for introduction of a substance into the body through anopening or the withdrawal of fluids therefrom, and referred to underterms such as antrum, colonic, elbowed, double-elbowed', curved,eustachian, faucial, female, in-dwelling, prostatic, or wingedcatheters, tubes, irrigators, and by other names.

Heretofore, catheters have been made of various materials showing adegree of flexibility, as thin metal tubing, rubber of varying stages ofvulcanization, and compounds in the liquid or semi-liquid conditionbuilt up over a web as of a fabric, usually by repeated dipping of thesame in a solution of the coating or impregnating material.

Metal-catheters are harsh todelicate membranes, prone to irritate andwound tissues upon insertion, especially when the tissues are ultra-'sensitive and unusually delicate, as in inflammatory and certainpathological processes and normal and pathologic secretions exert asolvent effect on the metal which with some metals is very marked. Theircomparatively low elasticity is also a disadvantage to their extensiveapplication,

especially in urological work such as urethral, ureteral and renalexploration and in connection with the removal of some forms of renalcalculi.

Catheters made of rubber vary greatly in elasticity and supplenessdependent upon the degree I of vulcanization to which the rubber hasbeen subjected. The soft rubber catheters are highly elastic, but moreor less porous and spongy, causing difiiculty in sterilization, andrequiring such rigid sterilization treatments as to materially shortentheir period of effectiveness. They also, in general, lack the requisiterigidity coupled with the desired flexibility to penetrate body canals,especially the ureter where thecanal diameter is relatively small andmore or less.

tortuous, and which may be constricted or even substantially closed bymeans of abnormal or other conditions present therein.

The hard rubber catheters while they may be of the desired rigidity, aredeficient in suppleness and pliability. The comparatively large amountsof sulfur and sulfur compounds contained therein, together with thevulcanization accelerators, many of which are nitrogen compounds ofpronounced toxicity, materially militate against their effectiveness andnarrow their range of safe applicability. Furthermore, hard rubbercatheters are prone to injure and wound delicate membranes which areoften extremely tender and susceptible due to irritations andinflammatory conditions so that the use of these catheters is materiallylimited, both as to scope of application and to the technique andexperience of the manipulator. Catheters are often used by the layman,sometimes daily, as in prostatic enlargement and analogouscomplications, and the unyielding property of vulcanized rubber ofteninitiates irritation, which, when continued,

may and does lead to serious chronic results.

Glass catheters, while usually of smooth surface, have a very lowelasticity and suppleness, and-there is always present the grave dangerof breakage or chipping ofi", especially where the glass wall is ofrelatively extreme thinness, as is sometimes the case. For this andother reasons, the use of glass catheters involves an element of danger,and in addition they have a limited and decreasing range ofapplicability. I

Enamel catheters, that is, catheters made of glazed porcelain, are usedto a limited extent. They are practically rigid with zero flexibility,of

relatively rough interior due to the difliculties of interior glazing,and very fragile in the thin'cell wall diameter as usually prepared. Byvirtue of' this inherent rigidity enamel catheters are useless foradaptation to the varying contour of the canal into which they areintended to be inserted, and

the rough interior introduces the danger of incomplete sterilization. I

One of the objects of my invention is to overcome and minimize theherein enumerated and other disadvantages, while still conserving thepoints of desirability of these instruments as aobjections are overcomeBy etherized cellulose as herein used, is to be understood commerciallyalkylated, arylated or aralkylated normal or modified cellulose, ashighly etherified methyl-, ethyl-, propyl-, butyl, or benzyl-cellu'lose,or mixtures of the same as examples. 1

For many purposes and depending upon the physical propertiesdesired inthe finished catheter, and its size, dimensions, wall thickness, etc.,the desired elasticity. suppleness, flexibility, stability, and freedomfrom objectionable features for the purposes for which it is intended, Imay use a single or a mixed cellulose ether or mixture of celluloseothers, and where additional suppleness, elasticity, etc, is desired,suitable plasticizers, fiexilizers softeners, extensifiers' orsuppleness-induc-ing components may be incorporated with the celluloseether in an amount and of a nature to impart the kind and degree ofcharacteristics desired. The highly etheri-fled ethylcelluloses andbenzyl-celluloses have been found especially useful in this connection,on account of the number and amount of suitable plastifying componentswhich may be harmoniously incorporated therewith to induce the specificproperties required and the extent of the same desired.

The cellulose ethers, as a class, are insoluble in, and notdetrlmentally affected by ptyalin, pepsin, trypsin, oleopsln, steapsin,and other body enzymes and fluids, the products elaborated in thegallbladder, liver and kidney, both those that are normal .to thehealthy body and those formed under pathological conditions; they can beproduced of a high degree of flexibility, and are not adversely affectedby the usual antiseptics, disinfectants, ba-ctericides, both those ofmetallic and non-metallic origin, usually applied for sterilizationpurposes.

As is well know-n, many of .the normal or pathological body secretionseither are distinctly acid in reaction as the hydrochloric acid in thegastric juice, the bile acids, uric acid and the like, while othersecretions are of pronounced alkaline reaction. These chemicallyreactive bodies often aided by enzymic action, exert an appreciabledissolving and decomposing effect upon a catheter or instrument ofanalogous use, when made of rubher or a cellulose ester, especiallywhere in some instances, the tubular surgical device: is left in thebody for an extended period as often is the case in drainage treatments.With the simple cellulose esters, as .the nitrate or the acetate, asaponifying action results, whereby a decomposition of the celluloseester takes place by a splitting off of acid radical.

As the culmination of a series of quantitative researches, thesurprising and unobvious observation has been made; that celluloseethers, and specifically the aralkylcelluloses of comparatively highdegree of arallqrlation, are substantially insoluble in and unaffectedby chemical and other components elaborated by or in the human body inhealth and disease.

This has been found to hold true to the maxierably in commercialprocesses, depending upon the nature of th etherifying process and theefficiency of the particular apparatus employed in the variousetherifying steps.

The available benzylcelluloses of commerce, insofar as aware, are not ofmaximum commercial degrees of benzylation. They are so benzy-lated as tomeet most of the technical requirements for which they are intended. Toprepare a benzylated cellulose of maximum etheriflcatlon, is arelatively expensive operation not justified by the usual requirementsof this cellulose ether in the lacquer and plastic arts.

It is recognized that in general, the water insolubility, swelling inthe presence of water or hydrous elements, and innocuousness to chemicalreagents, gradually increases as additional benzyl possible with suchrigid,

mum degree when benzyl cellulose is the an'allnvlcellulose employed, andwhere the benzylaltion has been allowed to proceed to commerciallymaximum etheriflcation, that is to say, where benzylation of thecellulose has resulted in the introduction of benzyl or benzoxy rests tothe extent of 75% to 95% of that theoretically possible, with theproduction of a cellulose ether substantially insoluble in water. Theword "maximum" as herein used in connection with the etheriflcaltion ofcellulose or other carbohydrate, varies considgroups or rests areintroduced into the cellulose aggregate, but heretofore no quantitativework has been done in determining the swelling, relative solubility andinn-ocu-ousness to normal and pathological fluids of benzylcellulosesapproaching the maximum in degree of benzylaltion. In the use of abenzylcel-lulose instrument of the catheter type, and in drainage afteroperations and for other purposes, especially in renal surgery I andtreatment for renal calculi, it often becomes necessary to allow theinstrument to remain for days and sometimes weeks in contact with highlysensitive membranes. In such conditions, it is paramount that thereshall be substantially no swelling of the catheter substance by thenormal and pathological fluids in which it is continually in contact.

Ordinary and so-called commercial tribenzylcelluloses are not suitablefor this purpose on account of the intumescing or solubilizlng action ofthe acid and alkaline body contents with which they are placed incontact in normal This limitation of their use in this important fieldwherein heretofore they have been found unsatisfactory, has beenovercome by me, by either benzylating cellulose with a. theoreticalexcess of benzy-l-ating agent under optimum conditions, orre-benzylalting the usual commercial benzylcelluloses to substantiallymaximum degree of benzylation;

Another valuable discovery made by me is that where the substantiallymaximum amount of benzyl is combined with cellulose, thermoplastlcizingbodies may be used wherein the softening point of the surgicalinstrument or catheter made therefrom, can be reduced to around thetemperature of the hum-an body. This advantage lies in the fact that therigidity of the catheter or similar instrument may be modified byinsertion in the bochr, so that exploratory work, especially inconnection with renal treatment and examinations may be made, whichwould be imnon-thermoplastic bodies, for example, as rubber. Thisknowledge is unobvious and only discovered by a combination oflaboratory investigation and clinical use.

The cellulose others as a body are characterized by relatively greatstability and apathy to reaction with chemical reagents, while stillcon-' serving an unusually high degree of inherent flexibility. Thecellulose ethers may be treated with. lye solutions of highconcentration with impunity, since there is no acid radical to swponifyof! by alkaline treatment as is the case with the simple celluloseesters, and in addition a-re inert to many chemicals which injuriouslyaffect rubber and other materials of which catheters of the present artare made.

It is impossible to increase the elasticity of rubber at will by theaddition oi products thereto, whereas with the cellulose ethers, byselection of the appropriate plastlfying agent or combination of thesame, and the ratio between plastifier and cellulose ether, there is avery wide range of flexibility and elasticity possible, which peculiarlyadapts the cellulose others for use in the catheter industry. Phenols,iodides and. other halogen inorganic or organic compounds of normalbactericidal concentration are inert in unfavorable action to thecellulose ethers of degree of etheriflcation comprehended herein.

The antiseptic, local anesthetic, fungicide, bacterlcide, medicament, orother addition of therapeutic value to the catheter substance may beincorporated therewith in' any approved manner, such, for instance, asdissolving the same in a relatively small amount of harmonious solventor solvent combina'non, incorporating th same with the etherizedcellulose in any approved manner as by malaxation, then preferablyremoving the volatile pontion by an evaporative step before extrusion,so that the medicament is uniformly disseminated throughout theetherized cellulose mass.

The etherized celluloses as a class are peculiarly adapted for useinthis connection by virtue of the fact that they maybe extruded inpractically non-porous condition, may be dyed, pigmented, or otherwisetreated without detrimentally' affecting their normal stability orusefulness; and the elasticity, being inherent in the cellulose etherbody, persists unchanged for an indefinite period of time. Therefore, awidely tained, especially as to elasticity, plasticity, suppleness andflexibility of the ethe and these inherent desirable properties may beconsiderably enhanced by the addition to the cellulose ethers ofsuitable plasticizing bodies now known to the cellulose ether art, suchas aliphatic and carbocylclic esters of lactic, glyooll-ic, tartaric,phthalic and'other acids, aryl phosphates, cyclohexanol esters,synthetic resinous bodim such as the halogenated diphenyls, thesubstituted sulfonamides, and the like.

A catheter, in general, may be considered as a tube, straight, curved,elbowed, etc., depending.

upon the use for which it is normally intended, and usually comprises anouter end or end held by the operator, which may be of the same exteriordiameter as the remainder of the tube portion or may be flared orotherwise enlarged; the opposite end called the tip or beak, being thatend intended ior insertion, and which may be of the same diameteras thetube portion, or may be smaller, and is usually made in many shapes andin a variety of ways. The tip may be a portion of the tube with one ormore orifices therein, or it may be a separate piece immovably attachedto the body of the catheter tube by means of an agglutinant, by i'usion,or in any other manner. The shape, configuration, length, and number oforifices therein, may vary considerably, depending upon the specific useto which the instrument is to be applied.

Having determined .the degree of ether properties intended from thedesired use forwhich the instrument is designed, the kind and nature ofcellulose other is selected, the amount and kind of thennoplasticlzingbody added if any be used, and the composition by means of solvents,nonsolvents and solvent and non-solvent combinations, is gelati-nized orcolioided to the degree re- 75 inch internal diameters. For colonicwork, a f

quired, and is then extruded through an orifice of appropriate size andshape. into tubular or other form. V

";-In general, it has been found the melting point 5 is naised and thedeleterious action 01' water on the cellulose ether decreases with thenumber of similar .or disslmilarradicals in the etherized cellulose. Forthe above and other reasons, I have obtained most satisfactoryresultsherein by employing a cellulose ether or cellulose ethersapproaching substantially as nearly as commercijally feasible, themaximum degree in etherifloation.

The exterior surface of the material may be modified as by smoothing,dipping in a cellulose ester, cellulose ether, or other lacquer orcoating composition, to increase the hardness, lessen the degree ofpermeability or for other reasonaafter which the tube portion isexpanded .or the diameter otherwise modified at the outer end, and thetip or beak portion may be punched, drilled.

or otherwise one or. more orifices placed therein after closingthe beakend, as with a cellulose ether composition, or a separate tip may bemade and ooapted onto the tube portion by means of an adhwive, byheat,'by heat and pressure, or in,

any other way, said tip being of the size and nature required for thespecific purpose intended. The number, size, spacing and location oforifices in the beak port-ion may be modified at will; I

The cellulose ether composition may be colored,

with dye or pigment or'both, to render the in- V strument distinctiveupon observation; it may 'be printed or lithngraphed upon, either underor on the final exterior coat if the extruded member is varying degreeof dwirable propenties may be ob subjected to a dipping process atterextrusion, or various antiseptics, remedial agents, analgesics or localanesthetics may be incorporated in the cellulose ether plastic mass toinduce a. thera- 40 peutic efie'ct on the organs with which the oathetermay normally be brought into contact. Urethral and especially ureteralcatheter explonations are usually relatively painful operations, so thatthe incorporation within the oatheter mass of local anesthetics,analgesics and the like, is often indicated.

Before extrusion in-to tubular form, and especially-where the instrumentis intended primarily for urological work as .with urethral and ureteralcatheters,.the cellulose other may have incorporated therewith andtherein, varying proportions of opacity inducing bodies oi value inX-ray work, such as bismuth salts (the normal nitrate or subnitrate),lead sulfates and lead salts,

5 barium salts such as barium sulfate or barium titanaite and othersalts or mixtures of salts suitable for this purpose. As an example,given for illustrative putposes only, I have found an Iexcellent'composition toothis purpose to be com- 'posed of 100 partscellulose ether plastic mass ness of the catheter tube. the nature ofthe opacity-inducing body used, and the particular roentgenologicaldiagnosis to be made.

Urethral catheters are usually flared on the outer end, substantiallyround, of exterior diameter 0.06 to 0.25 inch, interior diametersumciently large usually to admit a ureteral catheter. Ureteralcatheters are; usually not flared on the outer end, 'and lvarying tubediameter from 0.04 to 0.10 inch external and about 0.015

round tip is usually used, the exterior diameter being up to 0.75 inchdiameter. An antrum catheter usually has an exterior diameter range of0.075 to 0.15 inch and a varying internal dimeter, The exterior andinterior diameters will. of course, be adjusted by theextrusionfoperation, taking into the consideration the amount, if any,of volatile solvent present and the relative volatility of theplasticizing portion added to the cellulose ether prior .to theextrusion operation. The shape of the catheter tip may varyconsiderably, as in the olive, round or whistle tips, as examples.

In general, the substantially maximum benzylated cellul'oses have arelatively highinherent thermoplasticity, which property may be,considerably augmented and varied in' degree by the incorporationtherewith of suitable known cellulose ether plasticizers andflexibility-inducing compounds, and still conserve the relatively high;

and permanent stability to, and insolubility in chemical reagents whichcharacterize the cellulose others in general.

Likewise, it has been plasticizing agents, the stability of theetherized cellulose may be augmented, the porosity diminished, and thesuppleness and flexibility materially increased, without concomitantlydecreasfound that by the use of certain cellulose ether pl'asticizingand thermo-;

mg otherwise valuable inherent characteristics. 0

There has been described a method of producing a catheter. by dippingthe core into a solution of cellulose-or other compound, drying thesame, thenrepeating the process until there has been built up on thetextile center or core a sufficient thickness of layers for the purposesintended. However, such constructed tubes are porous, they have pinholesand blisters therein which increase the natural porosity, as comparedwith the cellulose ether composition of the nature as herein set forthwhich has been compacted by the necessarily high pressure involved inthe extrusion operation to a unitary non-porous whole, and is composedof a unitary material With a fabric core catheter built up in the manheras above indicated, there is tendency upon use for the textile core tobecome frayed, and a fragment may be broken off and remain in thebladder or kidney, nidus around which a calculus may form.

Therefore, the catheter involved in this invention is of homogeneousstructure throughout, and there is no dissimilar material core which maythroughout its substance.

thus providing a nucleus or first forming a textile core,

catheter may be dipped, sprayed,

-cized etherized cellulose so as to break off, fray or cause animpediment in X-ray work or similar investigation, on account ofvaria'tlon of opacity.

At the close of the extrusion operation, the or otherwise coated with acellulose compound in solution, and the instrument may be smoothed,polished, printed upon or otherwise treated to produce a finishedappearing instrument. The printing operation may be conducted upon theextruded cellulose compound, catheter is coated withafluid compound, andeither before or after the polishing or other finishing operation.

What I claim is:

1. A tubular surgical device comprising a plasticized etherizedcellulose, of-commercially maximum degree of etherification.

2. A smooth tubular surgical device comprising a plasticized ether-izedcellulose of maximum degree of etheriflcation.

3. A tubular surgical device comprising an .analkylated cellulose, ofmaximum commercial de gree of aralkylation.

4. A smooth flexible, tubular surgical device of homogeneous structure,said device comprising a thermoplastic aralkylated cellulose, of maximumcommercial degree of aralkylation.

5. A catheter comprising a benzylcellulose, of commercially maximumdegree of benzylation,

6. A catheter comprising a thermoplasticized benzyl-ated cellulose ofcommercially maximum degree of benzylation.

'7. A catheter comprising a thermoplastic, smooth, water-insolublebenzylated cellulose of commercially maximum d ree of etheriflcation,not adversely affected by the normal or pathological fluids of the body.

8. A catheter comprising a relatively long, hollow tube of smallexternal diameter formed by extrusion from a thermoplastic mass ofplastibe externally smooth, continuous, non-porous and highly flexiblebut having sufllcien-t inherent tensile strength and longitudinalrigidity to perm-it insertion by itself into and through long, narrowand tortuous bodily passages, the degree of etherification of said massbeing so high as to render said catheter water-insoluble and unaffectedby moisture, substantially inert to bodily fluids and medicaments and tohave the other inherent characteristics aforesaid.

VINCENT JEROME FLYNN.

either before or after the

